6-Keto prostaglandin F1α and analogs for treating dry eye

ABSTRACT

Compositions and methods for the treatment of dry eye and related diseases utilizing 6-keto-PGF 1α  and its analogs are disclosed.

RELATED APPLICATIONS

This is a national application under 35 U.S.C. §371 of PCT/US0035442filed Dec. 22, 2000, which draws priority from U.S. ProvisionalApplication Serial No. 60/171,736 filed Dec. 22, 1999, now abandoned.

FIELD OF THE INVENTION

The present invention relates to the use of 6-keto PGF_(1α) and analogsthereof to stimulate mucin secretion to treat dry eye,keratoconjunctivitis, Sjogren's syndrome and related ocular surfacediseases.

BACKGROUND OF THE INVENTION

Dry eye is a common ocular surface disease afflicting millions of peoplein the U.S. each year, especially the elderly (Schein et. al.,Prevalence of dry eye among the elderly. American J. Ophthalmology,124:723-738, (1997)). Dry eye may afflict an individual with varyingseverity. In mild cases, a patient may experience burning, a feeling ofdryness, and persistent irritation such as is often caused by smallbodies lodging between the eye lid and the eye surface. In severe cases,vision may be substantially impaired. Other diseases, such as Sjogren'sdisease and cicatricial pemphigoid manifest dry eye complications.

Although it appears that dry eye may result from a number of unrelatedpathogenic causes, the common end result is the breakdown of the tearfilm, which results in dehydration of the exposed outer surface of theeye. (Lemp, Report of the Nation Eye Institute/Industry Workshop onClinical Trials in Dry Eyes, The CLAO Journal, 21(4):221-231 (1995)).Four events have been identified which singly or in combination arebelieved to result in the dry eye condition: a) decreased tearproduction or increased tear evaporation; b) decreased conjunctivalgoblet-cell density; c) increased corneal desquamation; and d)destabilization of the cornea-tear interface (Gilbard, Dry eye:pharmacological approaches, effects, and progress. The CLAO Journal,22:141-145 (1996)). Another major problem is the decreased mucinproduction by the conjunctival cells and/or corneal epithelial cells ofmucin, which protects and lubricates the ocular surface (Gipson andInatomi, Mucin genes expressed by ocular surface epithelium. Progress inRetinal and Eye Research, 16:81-98 (1997)).

Practitioners have taken several approaches to the treatment of dry eye.One common approach has been to supplement and stabilize the ocular tearfilm using so-called artificial tears instilled throughout the day.Another approach has been the use of ocular inserts that provide a tearsubstitute or to stimulate endogenous tear production.

Examples of the tear substitution approach include the use of buffered,isotonic saline solutions, aqueous solutions containing water solublepolymers that render the solutions more viscous and thus less easilyshed by the eye. Tear reconstitution is also attempted by providing oneor more components of the tear film such as phospholipids and oils.Examples of these treatment approaches are disclosed in U.S. Pat. Nos.4,131,651 (Shah et. al.), 4,370,325 (Packman), 4,409,205 (Shively),4,744,980 and 4,883,658 (Holly), 4,914,088 (Glonek), 5,075,104 (Gresselet. al.) and 5,294,607 (Glonek et. al.).

United States Patents directed to the use of ocular inserts in thetreatment of dry eye include U.S. Pat. No. 3,991,759 (Urquhart). Othersemi-solid therapy has included the administration of carrageenans (U.S.Pat. No. 5,403,841, Lang) which gel upon contact with naturallyoccurring tear film.

Another recent approach involves the provision of lubricating substancesin lieu of artificial tears. U.S. Pat. No. 4,818,537 (Guo) discloses theuse of a lubricating, liposome-based composition.

Aside from the above efforts, which are directed primarily to thealleviation of symptoms associated with dry eye, methods andcompositions directed to treatment of the dry eye condition have alsobeen pursued. For example, U.S. Pat. No. 5,041,434 (Lubkin) disclosesthe use of sex steroids, such as conjugated estrogens, to treat dry eyecondition in post-menopausal women; U.S. Pat. No. 5,290,572 (MacKeen)discloses the use of finely divided calcium ion compositions tostimulate tear film; and U.S. Pat. No. 4,966,773 (Gressel et. al.)discloses the use of microfine particles of one or more retinoids forocular tissue normalization.

Although these approaches have met with some success, problems in thetreatment of dry eye nevertheless remain. The use of tear substitutes,while temporarily effective, generally requires repeated applicationover the course of a patient's waking hours. It is not uncommon for apatient to have to apply artificial tear solution ten to twenty timesover the course of the day. Such an undertaking is not only cumbersomeand time consuming, but is also potentially very expensive.

The use of ocular inserts is also problematic. Aside from cost, they areoften unwieldy and uncomfortable. Further, as foreign bodies introducedin the eye, they can be a source of contamination leading to infections.In situations where the insert does not itself produce and deliver atear film, artificial tears must still be delivered on a regular andfrequent basis.

In view of the foregoing, there is a clear need for an effectivetreatment for dry eye that is capable of alleviating symptoms, as wellas treating the underlying physical and physiological deficiencies ofdry eye, and that is both convenient and inexpensive to administer.

Mucins are proteins which are heavily glycosylated withglucosarnine-based moieties. Mucins provide protective and lubricatingeffects to epithelial cells, especially those of mucosal membranes.Mucins have been shown to be secreted by vesicles and discharged on thesurface of the conjuctival epithelium of human eyes (Greiner et. al.,Mucus Secretory Vesicles in Conjunctival Epithelial Cells of Wearers ofContact Lenses, Archives of Ophthalmology, 98:1843-1846 (1980); andDilly et. al., Surface Changes in the Anaesthetic Conjunctiva in Man,with Special Reference to the Production of Mucus from a Non-Goblet-CellSource, British Journal of Ophthalmology, 65:833-842 (1981)). A numberof human-derived mucins which reside in the apical and subapical cornealepithelium have been discovered and cloned (Watanabe et. al., HumanCorneal and Conjuctival Epithelia Produce a Mucin-Like Glycoprotein forthe Apical Surface, Investigative Ophthalmology and Visual Science(IOVS), 36(2):337-344 (1995)). Recently, a new mucin was reported to besecreted via the cornea apical and subapical cells as well as theconjunctival epithelium of the human eye (Watanabe et. al., IOVS,36(2):337-344 (1995)). These mucins provide lubrication, andadditionally attract and hold moisture and sebacious material forlubrication and the corneal refraction of light.

Mucins are also produced and secreted in other parts of the bodyincluding lung airway passages, and more specifically from goblet cellsinterspersed among tracheal/bronchial epithelial cells. Certainarachidonic acid metabolites have been shown to stimulate mucinproduction in these cells. Yanni reported the increased secretion ofmucosal glycoproteins in rat lung by hydroxyeicosatetraenoic acid(“HETE”) derivatives (Yanni et. al., Effect of IntravenouslyAdministered Lipoxygenase Metabolites on Rat Trachael Mucous Gel LayerThickness, International Archives of Allergy And Applied Immunology,90:307-309 (1989)).

The conventional treatment for dry eye, as discussed above, includesadministration of artificial tears to the eye several times a day. Otheragents claimed for increasing ocular mucin and/or tear productioninclude vasoactive intestinal polypeptide (Dartt et. al., Vasoactiveintestinal peptide-stimulated glycocongfugate secretion fromconjunctival goblet cells. Experimental Eye Research, 63:27-34, (1996)),gefarnate (Nakmura et. al., Gefarnate stimulates secretion of mucin-likeglycoproteins by corneal epithelium in vitro and protects cornealepithelium from dessication in vivo, Experimental Eye Research,65:569-574 (1997)), and the use of liposomes (U.S. Pat. No. 4,818,537),androgens (U.S. Pat. No. 5,620,921), melanocycte stimulating hormones(U.S. Pat. No. 4,868,154), phosphodiesterase inhibitors (U.S. Pat. No.4,753,945), retinoids (U.S. Pat. No. 5,455,265) andhydroxyeicosatetraenoic acid derivatives (U.S. Pat. No. 5,696,166).However, many of these compounds or treatments suffer from a lack ofspecificity, efficacy and potency and none of these agents have beenmarketed so far as therapeutically useful products to treat dry eye andrelated ocular surface diseases. Thus, there remains a need for anefficacious therapy for the treatment of dry eye and related diseases.

Prostaglandins are metabolite derivatives of arachidonic acid.Arachidonic acid in the body is converted to prostaglandin G₂, which issubsequently converted to prostaglandin H₂. Other naturally occurringprostaglandins are derivatives of prostaglandin H₂. A number ofdifferent types of prostaglandins are known in the art including A, B,C, D, E, F, G, I and J-Series prostaglandins (U.S. Pat. No. 5,151,444;EP 0 561 073 A1; Coleman et. al., VIII International Union ofPharmacology classification of prostanoid receptors: Properties,distribution, and structure of the receptors and their subtypes,Pharmacological Reviews, 45:205-229 (1994)). Depending on the number ofdouble-bonds in the α-(top chain) and/or the ω-chain (bottom chain), theprostaglandins are further classified with subscripts such as PGD₂,PGE₁, PGE₂, PGF_(2α), etc. (U.S. Pat. No. 5,151,444; Coleman et. al.,VIII International Union of Pharmacology classification of prostanoidreceptors: Properties, distribution, and structure of the receptors andtheir subtypes, Pharmacological Reviews, 45:205-229 (1994)). Whilstthese classes of prostaglandins interact preferably with the designatedmajor classes of receptors (e.g. DP, EP, FP) and subclasses of receptors(e.g. EP₂, EP₃, EP₄), the subscripts associated with the prostaglandindoes not necessarily correspond with the subclass of the receptor(s)with which they interact. Furthermore, it is well known that theseendogenous prostaglandins are non-specific in terms of interacting withthe various classes of prostaglandin receptors. Thus, the naturalprostaglandin PGE₂ not only interacts with EP₂ receptors, but can alsoactivate EP₁, EP₃ and EP₄ receptors (Coleman et. al., VIII InternationalUnion of Pharmacology classification of prostanoid receptors:Properties, distribution, and structure of the receptors and theirsubtypes, Pharmacological Reviews, 45:205-229 (1994)).

The compound 6-keto-PGF_(1α)(1) is a known stable hydrolysis product ofPGI₂ in mammals, and is frequently used as a marker for thedetermination of PGI₂ in blood and urine (Prostaglandins and RelatedSubstances: A Practical Approach; C. Benedetto, R. G. McDonald-Gibson,S. Nigam, and T. F. Slater, Eds.; IRL Press: Oxford, 1987, pp. 13-16).Recently, it has been found that 6-keto PGF_(1α) is a potent chloridesecretagogue released by intestinal epithelial cells in response tohypoxia [Colgan et. al., J. Clin. Invest., 102:1161(1998)]. Of interestin the present invention are 1 and its structural analogs.

SUMMARY OF THE INVENTION

The present invention is directed to compositions and methods for thetreatment of dry eye and other disorders requiring the wetting of theeye. More specifically, the present invention discloses compositionscontaining 6-keto PGF_(1α) and its analogs, and methods of their use fortreating dry eye type disorders.

Preferred compositions include an effective amount of 6-keto PGF_(1α) oran analog thereof for the production of mucins. The compositions areadministered topically to the eye for the treatment of dry eye.

DETAILED DESCRIPTION OF THE INVENTION

It has now been discovered that 6-keto PGF_(1α)and its analogs stimulatemucin production in human conjuctival epithelium and are thereforebelieved to be useful in treating dry eye. Specifically included arecompounds of the following formula I:

wherein:

R¹ is (CH₂)_(p)CO₂R, (CH₂)_(p)OR², (CH₂)_(p)COT, or (CH₂)_(p)T, where:

R is H or pharmaceutically acceptable cationic salt moiety, or CO₂Rforms a pharmaceutically acceptable ester moiety;

OR² forms a free or functionally modified hydroxy group, where R² ispreferably H, alkyl, acyl, or aryl;

T comprises a free or functionally modified amino group and ispreferably NR³R⁴

where R³ and R⁴, are the same or different and are selected from thegroup consisting of H, alkyl, aryl, acyl, alkoxycarbonyl, alkoxy,aminocarbonyl, and hydroxy; and

p is 0 or 2;

Q⁹ and Q¹¹ form a free or functionally modified hydroxy group and arepreferably R⁹O and R¹¹O, respectively, where R⁹ and R¹¹ are the same ordifferent and are preferably H, alkyl, acyl, or aryl;

X—Y is CH₂CH₂, trans-CH═CH, or C≡C;

one of A, B is H and the other comprises a free or functionally modifiedhydroxy group, or A-B together are the oxygen of a carbonyl group; and

D is cycloalkyl, C₅₋₈ alkyl, (CH₂)_(q)Ar or (CH₂)_(q)OAr; where q is1-6; and

Ar is a phenyl ring optionally substituted with alkyl, halo,trihalomethyl, alkoxy, acyl, acyloxy, amino, alkylamino, acylamino, orhydroxy; or

D is (CH₂)_(p)Ar¹; where p is 0-6; and

wherein:

W is CH₂, O, S(O)_(m), NR¹⁰, CH₂CH₂, CH—CH, CH₂O, CH₂S(O)_(m), CH—N, orCH₂NR¹⁰; where m is 0-2, and R¹⁰ is H, alkyl, or acyl; Z is H, alkyl,alkoxy, acyl, acyloxy, halo, trihalomethyl, amino, alkylamino,acylamino, or hydroxy; and

is single or double bond.

It is believed that the compounds of formula I wherein D is selectedfrom the group consisting of (CH₂)_(q)Ar, (CH₂)_(q)OAr, (CH₂)_(p)Ar¹,and cycloalkyl, where p, q, Ar, and Ar¹ are as defined above, are novel.

It is appreciated that those compounds of formula I wherein R⁹ is H(i.e., where a hydroxyl group is present at carbon 9) exist as anequilibrium mixture of ketoalcohol i and hemiketal ii isomers, with thelatter usually being the predominant or even exclusive isomer. Bothforms are included within the scope of the invention. For convenience,only the ketoalcohol form is depicted in the specification and claims.

Included within the scope of the present invention are the individualenantiomers of the compounds of the present invention, as well as theirracemic and non-racemic mixtures. The individual enantiomers can beenantioselectively synthesized from the appropriate enantiomericallypure or enriched starting material by means such as those describedbelow. Alternatively, they may be enantioselectively synthesized fromracemic/non-racemic or achiral starting materials. (AsymmetricSynthesis; J. D. Morrison and J. W. Scott, Eds.; Academic PressPublishers: New York, 1983-1985, volumes 1-5; Principles of AsymmetricSynthesis; R. E. Gawley and J. Aube, Eds.; Elsevier Publishers:Amsterdam, 1996). They may also be isolated from racemic and non-racemicmixtures by a number of known methods, e.g. by purification of a sampleby chiral HPLC (A Practical Guide to Chiral Separations by HPLC; G.Subramanian, Ed.; VCH Publishers: New York, 1994; Chiral Separations byHPLC; A. M. Krstulovic, Ed.; Ellis Horwood Ltd. Publishers, 1989), or byenantioselective hydrolysis of a carboxylic acid ester sample by anenzyme (Ohno, M.; Otsuka, M. Organic Reactions, volume 37, page 1(1989)). Those skilled in the art will appreciate that racemic andnon-racemic mixtures may be obtained by several means, including withoutlimitation, nonenantioselective synthesis, partial resolution, or evenmixing samples having different enantiomeric ratios. Departures may bemade from such details within the scope of the accompanying claimswithout departing from the principles of the invention and withoutsacrificing its advantages. Also included within the scope of thepresent invention are the individual isomers substantially free of theirrespective enantiomers.

As used herein, the terms “pharmaceutically acceptable salt” and“pharmaceutically acceptable ester/pharmaceutically acceptablethioester” means any salt, ester, or thioester, respectively, that wouldbe suitable for therapeutic administration to a patient by anyconventional means without significant deleterious health consequences;and “ophthalmically acceptable salt”, “ophthalmically acceptable ester”,and “ophthalmically acceptable thioester” means any pharmaceuticallyacceptable salt, ester, or thioester, respectively, that would besuitable for ophthalmic application, i.e. non-toxic and non-irritating.

The term “free hydroxy group” means an OH. The term “functionallymodified hydroxy group” means an OH which has been functionalized toform: an ether, in which an alkyl, aryl, cycloalkyl, heterocycloalkyl,alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, or heteroaryl groupis substituted for the hydrogen; an ester, in which an acyl group issubstituted for the hydrogen; a carbamate, in which an aminocarbonylgroup is substituted for the hydrogen; or a carbonate, in which anaryloxy-, heteroaryloxy-, alkoxy-, cycloalkoxy-, heterocycloalkoxy-,alkenyloxy-, cycloalkenyloxy-, heterocycloalkenyloxy-, oralkynyloxy-carbonyl group is substituted for the hydrogen. Preferredmoieties include OH, OCH₂C(O)CH₃,OCH₂C(O)C₂H₅, OCH₃, OCH₂CH₃, OC(O)CH₃,and OC(O)C₂H₅.

The term “free amino group” means an NH₂. The term “functionallymodified amino group” means an NH₂ which has been functionalized toform: an aryloxy-, heteroaryloxy-, alkoxy-, cycloalkoxy-,heterocycloalkoxy-, alkenyl-, cycloalkenyl-, heterocycloalkenyl-,alkynyl-, or hydroxy-amino group, wherein the appropriate group issubstituted for one of the hydrogens; an aryl-, heteroaryl-, alkyl-,cycloalkyl-, heterocycloalkyl-, alkenyl-, cycloalkenyl-,heterocycloalkenyl-, or alkynyl-amino group, wherein the appropriategroup is substituted for one or both of the hydrogens; an amide, inwhich an acyl group is substituted for one of the hydrogens; acarbamate, in which an aryloxy-, heteroaryloxy-, alkoxy-, cycloalkoxy-,heterocycloalkoxy-, alkenyl-, cycloalkenyl-, heterocycloalkenyl-, oralkynyl-carbonyl group is substituted for one of the hydrogens; or aurea, in which an aminocarbonyl group is substituted for one of thehydrogens. Combinations of these substitution patterns, for example anNH₂ in which one of the hydrogens is replaced by an alkyl group and theother hydrogen is replaced by an alkoxycarbonyl group, also fall underthe definition of a functionally modified amino group and are includedwithin the scope of the present invention. Preferred moieties includeNH₂, NHCH₃, NHC₂H₅, N(CH₃)₂, NHC(O)CH₃, NHOH, and NH(OCH₃).

The term “acyl” represents a group that is linked by a carbon atom thathas a double bond to an oxygen atom and a single bond to another carbonatom.

The term “alkyl” includes straight or branched chain aliphatichydrocarbon groups that are saturated and have 1 to 15 carbon atoms. Thealkyl groups may be interrupted by one or more heteroatoms, such asoxygen, nitrogen, or sulfur, and may be substituted with other groups,such as halogen, hydroxyl, aryl, cycloalkyl, aryloxy, or alkoxy.Preferred straight or branched alkyl groups include methyl, ethyl,propyl, isopropyl, butyl and t-butyl.

The term “cycloalkyl” includes straight or branched chain, saturated orunsaturated aliphatic hydrocarbon groups which connect to form one ormore rings, which can be fused or isolated. The rings may be substitutedwith other groups, such as halogen, hydroxyl, aryl, aryloxy, alkoxy, orlower alkyl. Preferred cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl.

The term “heterocycloalkyl” refers to cycloalkyl rings that contain atleast one heteroatom such as O, S, or N in the ring, and can be fused orisolated. The rings may be substituted with other groups, such ashalogen, hydroxyl, aryl, aryloxy, alkoxy, or lower alkyl. Preferredheterocycloalkyl groups include pyrrolidinyl, tetrahydrofuranyl,piperazinyl, and tetrahydropyranyl.

The term “alkenyl” includes straight or branched chain hydrocarbongroups having 1 to 15 carbon atoms with at least one carbon—carbondouble bond, the chain being optionally interrupted by one or moreheteroatoms. The chain hydrogens may be substituted with other groups,such as halogen. Preferred straight or branched alkeny groups include,allyl, 1-butenyl, 1-methyl-2-propenyl and 4-pentenyl.

The term “cycloalkenyl” includes straight or branched chain, saturatedor unsaturated aliphatic hydrocarbon groups which connect to form one ormore non-aromatic rings containing a carbon—carbon double bond, whichcan be fused or isolated. The rings may be substituted with othergroups, such as halogen, hydroxyl, alkoxy, or lower alkyl. Preferredcycloalkenyl groups include cyclopentenyl and cyclohexenyl.

The term “heterocycloalkenyl” refers to cycloalkenyl rings which containone or more heteroatoms such as O, N, or S in the ring, and can be fusedor isolated. The rings may be substituted with other groups, such ashalogen, hydroxyl, aryl, aryloxy, alkoxy, or lower alkyl. Preferredheterocycloalkenyl groups include pyrrolidinyl, dihydropyranyl, anddihydrofuranyl.

The term “carbonyl group” represents a carbon atom double bonded to anoxygen atom, wherein the carbon atom has two free valencies.

The term “aminocarbonyl” represents a free or functionally modifiedamino group bonded from its nitrogen atom to the carbon atom of acarbonyl group, the carbonyl group itself being bonded to another atomthrough its carbon atom.

The term “lower alkyl” represents alkyl groups containing one to sixcarbons (C₁-C₆).

The term “halogen” represents fluoro, chloro, bromo, or iodo.

The term “aryl” refers to carbon-based rings which are aromatic. Therings may be isolated, such as phenyl, or fused, such as naphthyl. Thering hydrogens may be substituted with other groups, such as loweralkyl, halogen, free or functionalized hydroxy, trihalomethyl, etc.Preferred aryl groups include phenyl, 3-(trifluoromethyl)phenyl,3-chlorophenyl, and 4-fluorophenyl.

The term “heteroaryl” refers to aromatic hydrocarbon rings which containat least one heteroatom such as O, S, or N in the ring. Heteroaryl ringsmay be isolated, with 5 to 6 ring atoms, or fused, with 8 to 10 atoms.The heteroaryl ring(s) hydrogens or heteroatoms with open valency may besubstituted with other groups, such as lower alkyl or halogen. Examplesof heteroaryl groups include imidazole, pyridine, indole, quinoline,furan, thiophene, pyrrole, tetrahydroquinoline, dihydrobenzofuran, anddihydrobenzindole.

The terms “aryloxy”, “heteroaryloxy”, “alkoxy”, “cycloalkoxy”,“heterocycloalkoxy”, “alkenyloxy”, “cycloalkenyloxy”,“heterocycloalkenyloxy”, and “alkynyloxy” represent an aryl, heteroaryl,alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl,heterocycloalkenyl, or alkynyl group attached through an oxygen linkage.

The terms “alkoxycarbonyl”, “aryloxycarbonyl”, “heteroaryloxycarbonyl”,“cycloalkoxycarbonyl”, “heterocycloalkoxycarbonyl”,“alkenyloxycarbonyl”, “cycloalkenyloxycarbonyl”,“heterocycloalkenyloxycarbonyl”, and “alkynyloxycarbonyl” represent analkoxy, aryloxy, heteroaryloxy, cycloalkoxy, heterocycloalkoxy,alkenyloxy, cycloalkenyloxy, heterocycloalkenyloxy, or alkynyloxy groupbonded from its oxygen atom to the carbon of a carbonyl group, thecarbonyl group itself being bonded to another atom through its carbonatom.

Preferred for purposes of the present invention are those compounds offormula I wherein:

R¹ is CO₂R, wherein R is H, or CO₂R forms an ophthalmically acceptablesalt or an ophthalmically acceptable ester moiety;

R⁹ and R¹¹ are H;

X—Y is CH₂CH₂, trans-CH═CH, or C≡C;

one of A, B═H, and the other is OH; and

D is n-C₅H₁₁, CH₂CH₂Ar, CH₂OAr, or cyclohexyl, where Ar is a phenyl ringoptionally substituted with halo or trihalomethyl.

Preferred novel compounds are those of formula I wherein:

R¹ is CO₂R, wherein R is H, or CO₂R forms an ophthalmically acceptablesalt or an ophthalmically acceptable ester moiety;

R⁹ and R¹¹ are H;

X—Y is CH₂CH₂, trans-CH═CH, or C≡C;

one of A, B═H, and the other is OH; and

D is CH₂CH₂Ar, CH₂OAr, or cyclohexyl, where Ar is a phenyl ringoptionally substituted with halo or trihalomethyl.

Among the most preferred of the foregoing compounds are the followingcompounds 1-6:

Compound 1 is commercially available from Cayman Chemical Co., AnnArbor, Mich. The syntheses of compounds 2 and 3 are disclosed in U.S.Pat. Nos. 4,205,178 and 4,158,667. Compounds 4-6 can be prepared asdetailed in examples 1-3 (below).

EXAMPLE 1

13E)-(9S, 11R,15S)-6-Oxo-17-phenyl-9,11,15-trihydroxy-18,19,20-trinor-13-prostenoicacid (4)

A CHCl₃ solution of 7-phenyl prostaglandin 7 (for the synthesis of 7 seeResul et. al., J. Med. Chem 36:2, 243 (1993), as described in Example1a, is treated with N-br mosuccinimide (NBS) to afford bromoether 8,which is reacted with 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU) in hottoluene to provide enol ether 9. Heating a THF/water solution of 9 andp-toluenesulfonic acid monohydrate (TsOH) ifords triol 10, which issaponified with LiOH in water/MeOH to give acid 4

EXAMPLE 1a

17-Phenyl-18,19,20-trinor-PGF_(2α) Isopropyl Ester (3b). DBU (0.37 g,2.43 mmol) was added dropwise to a stirred solution of 3a (0.40 g, 0.81mol) in acetone (16 mL) at 0° C. The mixture was allowed to arm to roomtemperature whereupon isopropyl iodide 0.41 g, 2.43 mmol) was addeddropwise. After being stirred for 10 h (TLC monitoring), the reactionwas quenched with water, the mixture was extracted with EtOAc (50 mL),and the extract was washed with brine (20 mL), citric acid 3% (30 mL)and finally sodium hydrogen carbonate 5% (2×20 mL). After drying withanhydrous sodium sulfate, the solvent was removed in vacuo and theresidual oil was chromatographe on silica gel using EtOAc as eluent.This afforded 0.34 g (80%) of the title compound as a colorless oil:R_(f)=0.24 (EtOA); [α]²⁰ _(D)=+33.49° (c=0.74, CH₃CN); ¹H NMR CDCl₃) δ1.2 (δ, 6 H (CH₃)₂), 1.46 (m, 1 H), 1.64 (m, 2H), 1.74-1.78 (dd, 1 H),1.85 (m, 2H), 1.78-1.9 (m, 2 H), 2.08 (m, 2H), 2.23 (t, 2 H, 2.24 (m, 2H), 2.27 (m, H), 2.3 (m, 1 H), 2.62-2.72 (m, 2), 3.9 (m, 1 H), 4.07 (t,1 H), 4.13 (m, 1 H), 4.9 (m, 1 H), 5.43-5.59 (m, 4 H), 7.1-7.3 (m, 5 H);¹³C NMR (CDCl₃) δ 173.3, 141.9, 128.3, 125.7, 134.6 (C db), 132.03 (Cdb), 129.6 (C db), 129.04 (C db), 78.01, 72.83, 71.50, 67.5 55.6, 42.9,38.70, 33.90, 31.70, 26.50, 25.50, 24.80, 21.76, 21.75.

EXAMPLE 2

(13E)-(9S, 11R,15R)-6-Oxo-16-phenoxy-9,11,15-trihydroxy-17,18,19,20-tetranor-13-prostenoicacid (5)

A CHCl₃ solution of 16-phenoxy prostaglandin 11 (commercially availablefrom Cayman Chemical Co.) is treated with NBS to afford bromoether 12,which is heated with DBU in toluene to give enol ether 13. Acidichydrolysis of 13 with TsOH in hot THF/water provides 5.

EXAMPLE 3

(13E)-(9S,11R,15S)-15-Cyclohexyl-6-oxo-9,11,15-trihydroxy-16,17,18,19,20-pentanor-13-prostenoicacid (6)

Treatment of a THF solution of Ph₃P⁺(CH₂)₄CO₂H Br³¹ in at 0° C. withKOBu followed by addition of a THF solution of lactol 14 (for thesynthesis of 14, see U.S. Pat. No. 5,807,892, the contents of which areincorporated herein) affords an intermediate diene acid, which istreated with 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU) and isopropyliodide in acetone to afford diene 15. A CHCl₃ solution of 15 is treatedwith NBS in THF to provide bromoether 16, which is reacted with DBU inhot toluene to give enol ether 17. Acid hydrolysis of 17 usingp-toluenesulfonic acid monohydrate in hot THF/water yields ketotriol 18,which is saponified with LiOH in MeOH/water to afford 6.

The 6-keto PGF_(1α)analogs of the present invention may be contained invarious types of pharmaceutical compositions, in accordance withformulation techniques known to those skilled in the art. In general,these compounds will be formulated in solutions for topical ophthalmicadministration. Solutions, suspensions and other dosage forms areparticularly preferred for the treatment of dry eye.

The ophthalmic compositions of the present invention will include one ormore compounds of the present invention in a pharmaceutically acceptablevehicle. Various types of vehicles may be used. Aqueous solutions aregenerally preferred, based on ease of formulation, biologicalcompatibility, as well as a patient's ability to easily administer suchcompositions by means of instilling one to two drops of the solutions inthe affected eyes. However, the compounds of the present invention mayalso be readily incorporated into other types of compositions, such assuspensions, viscous or semi-viscous gels, or other types of solid orsemi-solid compositions. Suspensions may be preferred for thosecompounds of the present invention which are less soluble in water. Theophthalmic compositions of the present invention may also includevarious other ingredients, such as buffers, preservatives, co-solventsand viscosity building agents.

An appropriate buffer system (e.g., sodium phosphate, sodium acetate orsodium borate) may be added to prevent pH drift under storageconditions.

Antioxidants may be added to compositions of the present invention toprotect the active ingredient from oxidation during storage. Examples ofsuch antioxidants include vitamin E and analogs thereof, ascorbic acidand butylated hydroxytoluene (BHT).

Ophthalmic products are typically packaged in multidose form.Preservatives are thus required to prevent microbial contaminationduring use. Suitable preservatives include: benzalkonium chloride,thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethylalcohol, edetate disodium, sorbic acid, polyquaternium-1, or otheragents known to those skilled in the art. Such preservatives aretypically employed at a level of from 0.001 to 1.0% weight/volume (“%w/v”).

In general, the doses used for the above described purposes will vary,but will be in an effective amount to increase mucin production in theeye and thus eliminate or improve dry eye conditions. As used herein,the term “pharmaceutically effective amount” refers to an amount whichimproves the dry eye condition in a human patient. When the compositionsare dosed topically, they will generally be in a concentration range offrom 0.001 to about 1.0% w/v, with 1-2 drops administered 1-4 times perday.

As used herein, the term “pharmaceutically acceptable carrier” refers toany vehicle which, when formulated, is safe, and provides theappropriate delivery for the desired route of administration of aneffective amount of at least one compound of the present invention.

The invention has been described by reference to certain preferredembodiments; however, it should be understood that it may be embodied inother specific forms or variations thereof without departing from itsspirit or essential characteristics. The embodiments described above aretherefore considered to be illustrative in all respects and notrestrictive, the scope of the invention being indicated by the appendedclaims rather than by the foregoing description.

What is claimed is:
 1. A method for the treatment of dry eye which comprises administering to a mammal a composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of one or more compounds of the following formula I:

wherein: R¹ is (CH₂)_(p)CO₂R, (CH₂)_(p)OR², (CH₂)_(p)COT, or (CH₂)_(p)T, where: R is H or pharmaceutically acceptable cationic salt moiety, or CO₂R forms a pharmaceutically acceptable ester moiety; OR² forms a free or functionally modified hydroxy group; T comprises a free or functionally modified amino group; and p is 0 or 2; Q⁹ and Q¹¹ form a free or functionally modified hydroxy group; X—Y is CH₂CH₂, trans-CH═CH, or C≡C; one of A, B is H and the other comprises a free or functionally modified hydroxy group, or A-B together are the oxygen of a carbonyl group; and D is cycloalkyl, C₅₋₈ alkyl, (CH₂)_(q)Ar or (CH₂)_(q)OAr; where q is 1-6; and Ar is a phenyl ring optionally substituted with alkyl, halo, trihalomethyl, alkoxy, acyl, acyloxy, amino, alkylamino, acylamino, or hydroxy; or D is (CH₂)_(p)Ar¹; where p is 0-6; and

 wherein: W is CH₂, O, S(O)_(m), NR¹⁰, CH₂CH₂, CH═CH, CH₂O, CH₂S(O)_(m), CH═N, or CH₂NR¹⁰; where m is 0-2, and R¹⁰ is H, alkyl, or acyl; Z is H, alkyl, alkoxy, acyl, acyloxy, halo, trihalomethyl, amino, alkylamino, acylamino, or hydroxy; and

is single or double bond.
 2. The method of claim 1, wherein the mammal is a human and the composition is administered topically,
 3. The method of claim 2, wherein for the one or more compounds of formula I: R¹ is CO₂R, wherein R is H, or CO₂R forms an ophthalmically acceptable salt or an ophthalmically acceptable ester moiety; Q⁹ and Q¹¹ are OH; X—Y is CH₂CH₂, trans-CH═CH, or C≡C; one of A, B═H, and the other is OH; and D is n-C₅H₁₁, CH₂CH₂Ar, CH₂OAr, or cyclohexyl, where Ar is a phenyl ring optionally substituted with halo or trihalomethyl.
 4. The method of claim 3, wherein the one or more compounds of formula I are selected from the group consisting of:


5. A compound of formula I:

wherein: R¹ is (CH₂)_(p)CO₂R², (CH₂)_(p)OR², (CH₂)_(p)COT, or (CH₂)_(p)T, where: R is H or pharmaceutically acceptable cationic salt moiety, or CO₂R forms a pharmaceutically cceptable ester moiety; OR² forms a free r functionally modified hydroxy group; T comprises a free or functionally modified amino group; and p is 0 or 2; Q⁹ and Q¹¹ form a free or functionally modified hydroxy group; X—Y is CH₂CH₂ or C≡C; one of A, B is H and the other comprises a free or functionally modified hydroxy group, or A-B together are the oxygen of a carbonyl group; and D is cycloalkyl; or D is (CH₂)_(q)Ar or (CH₂)_(q)OAr; where q is 1-6; and Ar is a phenyl ring optionally substituted with alkyl, halo, trihalomethyl, alkoxy, acyl, acyloxy, amino, alkylamino, acylamino, or hydroxy; or D is (CH₂)_(p)Ar¹; where p is 0-6; and

 wherein: W is CH₂, O, S(O)_(m), NR¹⁰, CH₂CH₂, CH═CH, CH₂O, CH₂S(O)_(m), CH═N, or CH₂NR¹⁰; where m is 0-2, and R¹⁰ is H, alkyl, or acyl; Z is H, alky, alkoxy, acyl, acyloxy, halo, trihalomethyl, amino, alkylamino, acylamino, or hydroxy; and ---- is single or double bond.
 6. The compound of claim 5, wherein: R¹ is CO₂R, wherein R is H, or CO₂R forms an ophthalmically acceptable salt or an ophthalmically acceptable ester moiety; Q⁹ and Q¹¹ are OH; X—Y is CH₂CH₂ or C≡C; one of A, B═H, and the other is OH; and D is CH₂CH₂Ar, CH₂OAr, pr cyclohexyl, where Ar is a phenyl ring optionally substituted with halo or trihalomethyl.
 7. A compound selected from the group consisting of: 